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Pharmacological aspects

Psychopharmacology of
anxiety disorders
Giovanni B. Cassano, MD; Nicolò Baldini Rossi, MD; Stefano Pini, MD


nxiety disorders are the most common and
among the most disabling of mental disorders in adults
and adolescents.1 Although many are highly circumscribed fears of mild-to-moderate severity, it has been
estimated by the Epidemiological Catchment Area
(ECA) study2 that approximately one quarter of people
will experience severe symptoms, disability, and handicap
as a consequence of anxiety disorders at some time during their lifetime. These disorders are associated with significant morbidity3 and increased mortality, probably as
a consequence of increased suicide rates among sufferers. The direct and indirect costs to the health service and
economy are considerable. Although persons who suffer
from anxiety disorders are high consumers of all types of
health services, only a minority receive specific help.4
The spectrum of anxiety disorders includes generalized
anxiety disorder (GAD), panic disorder (PD) and agoraphobia, obsessive-compulsive disorder (OCD), phobic
disorder (including social phobia), and posttraumatic
stress disorder (PTSD). With the discovery of new psychotropic medications, specific diagnosis within this spectrum is essential because each of these disorders
responds to specific pharmacotherapy. The approach to
anxiety should also recognize that anxiety and depression are often comorbid conditions.
Selective serotonin reuptake inhibitors (SSRIs), which
were designed to treat depression, are also effective for
many anxiety disorders. They have revolutionized the
treatment of anxiety, replacing chronic use of benzodiazepines (BZs). SSRIs are effective for OCD, PDs,

Exposure of the general population to a 1:4 lifetime risk of
disabling anxiety has inspired generations of fundamental
and clinical psychopharmacologists, from the era of the
earliest benzodiazepines (BZ) to that of the selective serotonin reuptake inhibitors (SSRIs) and related compounds,
eg, the serotonin and norepinephrine reuptake inhibitors
(SNRIs). This comprehensive practical review summarizes
current therapeutic research across the spectrum of individual disorders: generalized anxiety disorder (GAD), panic
disorder (PD) and agoraphobia (social anxiety disorder),
compulsive disorder (OCD), phobic disorder (including
social phobia), and posttraumatic stress disorder (PTSD).
Specific diagnosis is a precondition to successful therapy:
despite substantial overlap, each disorder responds preferentially to specific pharmacotherapy. Comorbidity with
depression is common; hence the success of the SSRIs,
which were originally designed to treat depression.
Assessment (multidomain measures versus individual end
points) remains problematic, as—frequently—do efficacy
and tolerability. The ideal anxiolytic remains the Holy Grail
of worldwide psychopharmacologic research.
Dialogues Clin Neurosci. 2002;4:271-285.

Author affiliations: Department of Psychiatry, Neurobiology, Pharmacology,
and Biotechnology, University of Pisa, Pisa, Italy
Keywords: generalized anxiety disorder; panic disorder; social anxiety disorder;
posttraumatic stress disorder; obsessive compulsive disorder; benzodiazepine;

Corresponding author: Stefano Pini, MD, Department of Psychiatry,
Neurobiology, Pharmacology, and Biotechnology, University of Pisa, Pisa, Italy


BZs should be avoided in patients with a past history of substance abuse. GAD OCD. sedation. they carry the risk of dependence. PD/AG Dizziness. GAD Nausea. but their dietary restrictions and side-effect profile have limited their use. depression Sedation.25 (bid) 0. panic disorder/agoraphobia. PD/AG.5-300 • Other medications Buspirone 5 (bid) 15-60 Propranolol 20 20-160 • Benzodiazepines Alprazolam 0. PTSD Nausea. PTSD. SAD. Doses of SSRIs for anxiety disorders could be higher than those used for depression. OCD. sedation.25-4 Lorazepam 0. nausea Depression. PTSD. GAD OCD. SAD. PTSD. PD/AG. The patient should be counseled that side effects often diminish with time and also that empirical switching to another SSRI may be necessary. GAD. withdrawal Somnolence. Food and Drug Administration. personality disorder. dry mouth. social anxiety disorder. 272 . and GAD (see Table I). somnolence Nausea. PTSD GAD. insomnia. and toxicity have made these medications less popular. insomnia. SAD. it works as well as BZs for GAD. ejaculation failure Nausea. SAD Table I. OCD. SAD. obsessive-compulsive disorder. dry mouth OCD.5 37. PD/AG. have proven effective in adjustment disorders in which both anxiety and depression are involved. fatigue. PTSD. PD/AG. monoamine oxidase inhibitors (MAOIs) are effective for anxiety. headache Nausea. GAD OCD. GAD. ejaculation failure PD/AG. PTSD. anorexia. insomnia. somnolence. insomnia. dry mouth Sedation. drowsiness. dizziness GAD. FDA.Also. Buspirone is a nonbenzodiazepine indicated for GAD. somnolence. Although they have the advantage of rapid onset of action.25-4 Clonazepam 0. It does not impair alertness and lacks abuse potential. Medication Starting Therapeutic dose range (mg) (mg/day) • Tricyclic antidepressants Clomipramine 25 25-250 Imipramine 10-25 150-300 • Selective serotonin reuptake inhibitors Citalopram 10 10-60 Fluoxetine 5-10 10-80 Fluvoxamine 50 50-300 Paroxetine 10 10-50 Sertraline 25 50-200 • Novel antidepressants Venlafaxine 37. sedation GAD Performance anxiety Drowsiness. dizziness GAD. Other antidepressants. are possible. SAD.Pharmacological aspects Selected abbreviations and acronyms BZ GABA GAD MAOI OCD PD PTSD RIMA SNRI SRI SSRI TCA benzodiazepine γ-aminobutyric acid generalized anxiety disorder monoamine oxidase inhibitors obsessive-compulsive disorder panic disorder posttraumatic stress disorder reversible inhibitor of monoamine oxidase A serotonin and norepinephrine reuptake inhibitor serotonin reuptake inhibitor selective serotonin reuptake inhibitor tricyclic antidepressant phobias. including tianeptine. anticholinergic side effects. somnolence. or dosage escalation. SAD. but has a slower onset of action and lacks sedative properties. PD/AG. but must be started at lower doses to minimize the shortterm agitation sometimes experienced with these medications.5 (tid) 1-6 Although tricyclic antidepressants (TCAs) have been used with success in anxiety disorders (Table I). BZs are the oldest class of medications used to treat anxiety. These medications are ideal for patients who experience infrequent bouts of anxiety or episodes of anxiety-related insomnia. PD/AG. even reactions as severe as delirium tremens. GAD. In head-to-head trials. and tolerance. PTSD PD/AG. dry mouth Nausea. A number of well-controlled clinical trials support the empirical evidence of effective pharmacotherapy of anx- Common side effects Indications (underscore indicates FDA approval) Weight gain. posttraumatic stress disorder. GAD OCD. PTSD. generalized anxiety disorder. PD/AG. Withdrawal syndromes resulting in rebound anxiety.25 (tid) 0. It is therefore less useful for the anxious patient who needs a sedative. GAD PD/AG. PD/AG. PTSD. Common medications used in the treatment of anxiety. PTSD.

11 and that low levels of depressive symptoms may predict a less favorable response to BZs.10 For example.9 Other data suggest that. oxazepam. 273 . and because of the high prevalence of comorbid depression. Generalized anxiety disorder Benzodiazepines Several studies have documented that BZs are more effective than placebo in GAD.Cassano et al iety disorders.20-22 and has been associated with maintenance of efficacy over a period of several months. It has been demonstrated to show efficacy in GAD10. Generalized anxiety disorder (GAD): therapeutic strategies. have a lower propensity to produce withdrawal symptoms. Pharmacological treatment evidence for each anxiety disorder will be briefly reviewed. or withdrawal. and their generally good tolerance9. however.13. discontinuation of acute treatment should be slow because of the potential for rebound anxiety and/or clinical relapse. in contrast to the almost immediate effects of BZs. TCA. with maximum effect achieved within 2 weeks. have little reinforcing potential. and its effect is usually not apparent until 2 to 3 weeks into treatment. which includes apprehensive worry and irritability. or likelihood of poor compliance. but tolerance to the anxiolytic effect of the BZs does not appear. tolerance. partly no doubt because of their rapid onset of action. diazepam and chlordiazepoxide. particularly the somatic/autonomic symptoms in contrast to the psychic symptom cluster. benzodiazepine.14-17 but since GAD is often a long-term and unremitting disorder. and current research into some new compounds is very active and promising. it is not associated with psychomotor impairment. First-line treatment Partial or no response BZ Buspirone Add or switch to a medication from a different class from the starting medication: SSRI or TCA or buspirone or BZ SSRI or TCA or trazodone Add buspirone or BZ Table II. there are few controlled data to support continued benefits of BZs in the long term in GAD. tricylic antidepressant.9-10. but less than two thirds will achieve remission of symptoms.19 With regard to dependence and withdrawal. No. However. SSRI.15. even if stopped abruptly. liability of abuse. Information from some 6 to 8 months’ maintenance therapy trials have found continued efficacy over time. while those with a long half-life. and an adequate pretreatment assessment should be an important step to evaluate whether a subject would be suitable for BZ therapy. several studies have shown that irritability may worsen in conjunction with high-potency BZs. psychic symptoms may be more responsive to other drugs altogether. Results generally show that approximately 70% of patients will respond to adequate BZ treatment (up to 40 mg/day of diazepam or equivalent for at least 3-4 Predominant clinical features • Somatic and autonomically driven symptoms • History of abuse absent • Sedation is needed • Psychic symptoms (apprehensive worry. for example. and it does not interact with alcohol.5-9 There is also evidence that BZs may be more effective on specific GAD symptoms. a partial 5-hydroxytryptamine (serotonin.Dialogues in Clinical Neuroscience . may need to continue for many years in a significant number of patients.12 Overall.Vol 4 . tolerance to side effects does occur. In long-term use. dependence. compounds with a slower onset of action. Azapirones The first pharmacological treatment for GAD beyond BZs was the azapirone buspirone. Anyway. BZs still remain a widely used treatment option for GAD. It is not sedating like the BZs. irritability) • Presence of history of abuse • Sedation is not needed or is contraindicated • Depressive symptoms are intermixed with anxiety • BZs or buspirone are contraindicated weeks). selective serotonin reuptake inhibitor. including previous history of withdrawal. For this reason. although they respond less well to BZs. BZ.18 it needs to be stated that pharmacotherapy. such as buspirone or imipramine. 2002 Psychopharmacology of anxiety disorders . tension. 3 .16 Buspirone is given in two or three divided doses up to 60 mg/day. attention has focused also on different medications and antidepressants as potential treatment for GAD (Table II). which decreases the function of postsynaptic 5-HT2 receptors. whether with BZs or other drugs. the ideal anxiolytic does not exist. for example. 5-HT)–1A (5-HT1A) agonist.

5 mg/day. and PTSD).29 and more recently flesinoxan and tandospirone.25 Patients who have had previous good responses to BZs do not appear to respond as well to buspirone. and dizziness were principally seen at the initiation of treatment and cleared up over time. Imipramine was more effective than diazepam on psychic anxiety symptoms.32 Hoehn-Saric et al. but with more equivocal results.38 Current trials have not established an optimal dosage for venlafaxine in the treatment of GAD.40 Other drugs Several other drugs have been assessed in GAD. with doses of 200 to 300 mg/day often being sufficient. subjects continued to improve over the 6-month period. which may also be benefi- cial in GAD. Although most of the improvement on venlafaxine occurred in the first 4 weeks.12 and Rickels et al9 have provided evidence for the benefit of imipramine and trazodone in GAD. Nefazodone enjoys the advantage of greater patient acceptability and tolerability than trazodone. Its reuptake-inhibiting effects on serotonin and norepinephrine confer a double advantage relative to some of the more selective compounds mentioned above.23 while it is less effective than BZs on somatic and autonomically driven symptoms. with buspirone (up to 30 mg/day). Another double-blind.31 have supported the possible efficacy of tricyclic drugs in GAD-like states. Trazodone. even if they appear to be better in treating psychic anxiety symptoms.27. a serotonin and norepinephrine reuptake inhibitor (SNRI). social phobia. and placebo in outpatients with GAD. but potentially effective drug for the disorder at doses of up to 400 mg/day. 150. data suggest that 75 to 150 mg/day is probably the most appropriate dosage range. their role in the treatment of GAD remains unclear. 5-HT2 antagonist. Antidepressants Although antidepressants are now well-established treatments of choice in several anxiety disorders (eg. OCD. has been the controlled comprehensive trials with venlafaxine. Further controlled trials by Kahn et al. PD.26 Other azapirone drugs have been assessed in GAD.30 Early retrospective analyses of subjects with anxiety neurosis21. withdrawal symptoms. In five placebo-controlled 8-week trials. notably the Hamilton Depression Scale anxiety subscore.36 These findings were replicated in a large 6-month trial evaluating long-term treatment of GAD. with positive results observed at dosages as low as 37. 8-week study compared venlafaxine (up to 150 mg/day). and weak adrenergic antagonist.22 probably due to the lack of sedative effect and inability to alleviate BZ withdrawal symptoms. apprehensive tension. largely out of consideration of the results of the studies with TCAs. Perhaps the obscurity of these findings relates to the general uncertainty about the nature of GAD. but can be a useful backup drug for more difficult to treat or nonresponsive patients. and irritability. due to its side-effect profile. and sedation. dry mouth. insomnia. Mild side effects including nausea. and the apparent belief that it is a highly placebo-responsive disorder.24. However. while BZs are probably superior in treating the somatic symptoms.39 The results of these studies indicate that antidepressants offer promise in GAD. but starting buspirone 2 to 3 weeks before tapering the BZs has produced better results. One open-label study in GAD has suggested benefit for this drug. Its hypnotic properties are also useful where insomnia is a major problem. The well-established anxiolytic effects of BZs are modified by several drawbacks. However.10 and where depressive symptoms are intermixed with anxiety. These BZ-like compounds 274 . but venlafaxine showed an earlier effect and advantage over buspirone in secondary outcome measures. Venlafaxine (75. and it would also be expected to have significant antidepressant effects. like gepirone. venlafaxine has demonstrated efficacy significantly greater than placebo in the treatment of GAD patients without accompanying depression.34 The most recent development in the pharmacotherapy of GAD. has also been found to be effective and remains a little-used.35. primarily of physical dependence. trazodone is unlikely to be a first choice.28 ipsapirone. its constantly changing criteria.37. and these improvements were maintained throughout the remainder of trials.Pharmacological aspects The drug works well when there are conspicuous symptoms of worry. Little attention has been given to the fact that several studies have provided encouraging support for their efficacy. a serotonin reuptake inhibitor (SRI) and 5-HT2 receptor antagonist. and 225 mg/day) produced greater effects than placebo after 1 week of the study. Nefazodone is a combined SRI. Both drugs were superior to placebo. The development of partial agonists at the γ-aminobutyric acid (GABA)/ BZ receptor complex offers some potential advantages over the traditional BZs.33 as is also the case for the SSRI paroxetine.

Potential problems with long-term use of BZs in PD are tolerance.50. After 5 weeks of treatment.58 Antidepressants Early in the 1960s. there is some evidence of withdrawal symptoms. has been reported to produce improvement in 60% to 90% of patients with GAD.51 with improvements also maintained in longer-term studies.61 Other TCAs also proved effective. The most comprehensively studied has been the β-carboline abecarnil. withdrawal. especially clomipramine. and the drug was well tolerated. No. TCA. In an initial double-blind trial. gabapentin) or switch to a TCA or a different SSRI (eventually try venlafaxine or reboxetine) Table III. 275 . imidazopyridine and β-carbolines.57. anecdotal experiences report potential value of kava and passionflower extract in the treatment of GAD. but a more recent study45 showed that it can be effective at low doses (50 mg/day) as well. SSRI. These newly developed compounds are either BZ derivatives or of a different chemical structure.Cassano et al should be effective anxiolytics. investigators documented that imipramine59 and the MAOIs. an antihistaminergic compound. particularly phenelzine. Further placebocontrolled studies42. and the improvement was not dependent on the treatment of concurrent affective symptoms. at higher doses. and efficacy was maintained without dose escalation. without withdrawal symptoms after short-term treatment.Vol 4 . such as clonazepam53 and lorazepam. but less likely to produce sedation. that is.44 It can be very sedating when high doses are used (50 and 100 mg qid). BZ.47-49 Panic disorder Benzodiazepines Alprazolam. Panic disorder (PD): therapeutic strategies. tolerance. selective serotonin reuptake inhibitor.52 Other high-potency BZs. a TCA.43 have shown modest treatment effects. however. Patients showed significant improvements in all major symptom areas. memory impairment. benzodiazepine. Hydroxyzine. avoidance behavior. but a 2.19 showed similar efficacy. lithium. and withdrawal symptoms on discontinuation.54 Although some studies have failed to observe a difference between alprazolam and imipramine in treatment of the common comorbid depressive symptoms. β-Blockers have been used for the treatment of some anxiety disorders. 2002 Psychopharmacology of anxiety disorders . gabapentin) SSRI Add a mood stabilizer (valproate. and then it was compared with both placebo and imipramine. lithium. clonazepam) Partial or no response Add a mood stabilizer (valproate. abuse liability. Following the demonstration of efficacy of the non-SSRI clomipramine.5-year naturalistic follow-up study found little evidence of tolerance to the antipanic effect of alprazolam. dependence. like number of panic attacks. tricylic antidepressant. and residual anxiety between attacks.55 several large meta-analyses have suggested a reduced efficacy for the BZs compared with TCAs56 and antidepressants in general (Table III). gabapentin) or switch to an SSRI (eventually try venlafaxine or reboxetine) Add an SSRI.Dialogues in Clinical Neuroscience . and ethanol potentiation. or a mood stabilizer (valproate. lithium.46 Finally. 86% of the patients improved compared with 47% with placebo. but the evidence so far does not support their use in GAD. Ballenger et al41 demonstrated clinical efficacy at doses in the range of 3 to 9 mg/day. 3 . BZs are usually well tolerated and they have a rapid onset of action (1-2 weeks). imipramine) High-potency BZ (alprazolam. the first licensed BZ for the treatment of panic.60 were both effective treatments of PD. was studied in a large multinational placebo-conPredominant clinical features • Mild symptoms • No cardiovascular system pathology or seizure history • SSRI intolerability • Severe symptoms • High frequency of attacks • Invalidating symptoms • History of abuse absent • SSRIs are not contraindicated trolled trial (Cross National Collaborative Panic Study) conducted in two 8-week phases: during the first it was compared with placebo. a number of large randomized trials have now demon- First-line treatment TCA (clomipramine.

The results.80 β-Blockers provided con- 276 . such as clonazepam or alprazolam.58 Improvement is seen as early as the first or second week with BZs and as early as the fourth week with the antidepressants.65 In patients who are treated for longer periods. three fourths of patients were free of panic attacks. and patients continue to improve for at least 3 to 6 months. in a review of 16 studies. again generally with little difference between treatments.” To initiate treatment at a very low dose. Although there are different responses of each of these symptoms to these treatments (eg. or to cover this first period with a high-potency BZ. Improvement in agoraphobic avoidance occurs with all the effective treatments. a selective norepinephrine reuptake inhibitor was effective and well tolerated in an 8-week.70. A recent effect-size analysis of controlled studies of treatment for PD also revealed no significant differences between SSRIs and older antidepressants in terms of efficacy or tolerability in short-term trials.69 69% of patients became free of avoidance. sertraline.76 and in a 8-week double-blind comparison with fluoxetine. the more complete and comprehensive is their response. renewed the interest in this class of agents.75 and mirtazapine provided good evidence both in an open-label study with a single-blind placebo run-in period. respectively.77 Reboxetine. successful treatments effectively reduce all these aspects of the PD syndrome. citalopram.Pharmacological aspects strated the efficacy of SSRIs in PD. double-blind trial. although this has not been rigorously studied. There is no standard measure employed in the literature of improvement in agoraphobic avoidance.71. In a large 12-month comparison of paroxetine and clomipramine.71 although improvement in agoraphobia is often the last portion of the syndrome to respond.64 Reduction of panic-attack frequency has been widely utilized. effective treatments reduce all the symptoms of PD. making comparisons across studies and treatments difficult.72 An important phenomenon in the early stages of treatment (both with TCAs and SSRIs) could be the paradoxical and transient increase in anxiety and number of panic attacks. In the large Cross-National Collaborative Panic Study.67 The anxiety that PD patients experience between panic attacks can be considerable.64 The percentage of patients who become free of panic attacks is generally 50% to 80% in acute trials lasting 6 to 8 weeks with various medications.66 after 8 to 12 months of treatment. probably more or less equally. although comparison trials between different SSRIs are generally lacking.56. the panic-free rates were 85% and 72%. and in a 12-month naturalistic study. This anxiety is reduced by all effective therapies with little difference between treatments. most effective treatments decrease the common comorbid depressive symptoms. The BZs are as effective as antidepressants in reducing avoidance. both in comparison with placebo and clomipramine.73 and another one failing to do so. It is generally true that the longer PD patients are treated.78 with a significant reduction in the mean number of panic attacks and phobic symptoms at doses of 6 to 8 mg/day. although effects begin earlier with the BZs. agoraphobic avoidance is the most difficult to treat). placebo-controlled.79 Pagoclone. paroxetine. Well-controlled trials provided evidence62 that fluvoxamine. rising from about 55% at 3 months. but appropriate outcome measures for PD still remain a problem. and fluoxetine have similar efficacies.74 A small case series suggested that venlafaxine may be effective in the treatment of PD. agoraphobic avoidance. could be useful approaches. Nonetheless. but the introduction of the reversible inhibitors of monoamine oxidase A (RIMAs). with an 8-week study showing efficacy for moclobemide in PD. the so-called “jittering syndrome. though. and most investigators now use multidomain measures. Dietary restrictions and side effects have limited the use of MAOIs.58 In a similar fashion. this percentage most often rises. and comorbid depression.63 As has been observed in all the trials. a cyclopyrrolone that is believed to act as a partial agonist at the GABAA/BZ receptor provided some preliminary evidence in a crossover trial with placebo. Although effective pharmacotherapy does significantly reduce agoraphobia avoidance. so far are conflicting. the frequency and severity of panic attacks. which is earlier than previously thought. in vivo exposure is often employed to reduce avoidance behaviors. such as moclobemide. Other drugs Buspirone in PD failed to show any efficacy even at high doses (60 mg/day). Recent trials suggest that a significant response to antidepressants may occur in the first 2 to 4 weeks. anxiety.65 Agoraphobia is probably the most treatment-resistant symptom in PD. but has been unreliable as a single measure.68 remission of ago- raphobia occurred in ranges varying from 18% to 64%.

117 Also the β-blocker atenolol. with 64% of patients obtaining clinically significant responses. Brofaromine (up to 150 mg/day) was promising and roughly comparable to moclobemide. although moclobemide was better tolerated.93 78%. Antidepressants Only anecdotal evidence supports the efficacy of TCAs for the treatment of social anxiety disorder.99-101 In multicenter. proved ineffective when tested in patient populations with generalized symptoms of social phobia.114. In a comparison between phenelzine and moclobemide. after the promising results of Versiani et al. Versiani et al87 conducted a 12-week. cognitive behavioral group therapy. placebo-controlled. despite early promise. Only 38% of patients on alprazolam were considered responders at end point compared with 69% on phenelzine.90.Vol 4 . 12-week trials in severely symptomatic patients with social phobia.89 There were three early controlled trials86. with response rates of 80%.91 in which phenelzine (up to 90 mg/day) was found to be quite effective. double-blind trial versus placebo.119 277 . with a response rate of 83% of patients on active drug versus 20% of patients on placebo.98 failed to confirm the efficacy of this drug in social anxiety.94 and 50%.97 as well a single study. 2002 Psychopharmacology of anxiety disorders . These positive findings were confirmed by Baldwin et al102 and Allgulander.88.2 mg/day) with phenelzine.88 mainly due to early observations that patients with atypical depression with marked interpersonal sensitivity and sociophobic features show a better response with MAOIs than TCAs.107 venlafaxine. Scores on the Liebowitz Social Anxiety Scale fell about 40% on paroxetine (30. in which Gelernter et al86 compared alprazolam (mean dose 4.118 Pindolol was no more effective than placebo in augmenting the effects of paroxetine treatment for generalized social phobia. which increased when treatment was extended to 4 months.105.Cassano et al flicting results.81 Initial evidence suggested that gabapentin82 and sodium valproate may be effective in PD.83 Also Ca-channel blockers have shown mixed results.108 and nefazodone. phenelzine was also better than alprazolam in terms of efficacy. These results were replicated by Heimberg et al92 in 1998. while carbamazepine is not. double-blind. the clinically significant response rates of patients were in the 42% to 77% range. with some positive small crossover trials.106 fluoxetine. Another large multicenter trial. Finally. 3 . but controlled studies are needed to confirm preliminary results.116 One controlled trial failed to find significant differences between buspirone and placebo.6 mg/day.109 In these trials. Differences were observed in the second week and throughout the remainder of the trial. double-blind study to compare bromazepam (mean dose 21 mg/day) to placebo. Other drugs Buspirone has been shown to be effective as a primary treatment in two thirds of patients in early trials. RIMAs have also been studied. As mentioned above. but appeared to work faster.104 sertraline. 24% on cognitive behavioral group therapy.96 in which 600 mg/day was superior to placebo (47% of responders compared with 34% receiving placebo).4 mg/day. 55% of patients had a marked or moderate response at a mean dosage of 36. 91% of the phenelzine patients versus 82% of moclobemide patients were nearly asymptomatic.91 By week 16. In the Gelernter et al86 trial.5 points). There has been only one double-blind study of alprazolam.115 as well as an augmenting agent with SSRIs.103 Other controlled trials with SSRIs include fluvoxamine. with 50% having a marked response and 50% having a moderate one. and 20% on placebo. Certainly the greatest amount of carefully controlled data are from the recent paroxetine studies. Clonazepam was shown to be effective in one 10-week.90. with 78% of patients responding to an average dosage of 2. No.85 Almost 85% of patients had some response.Dialogues in Clinical Neuroscience . and placebo over a 12-week period.95 Moclobemide. phenelzine appeared roughly equivalent. open trials of citalopram110-112 and buproprion113 have suggested that these drugs may be effective in the treatment of social anxiety disorder.84 Social anxiety disorder Benzodiazepines There is a limited number of controlled studies testing BZs in the treatment of social anxiety disorder. but a negative double-blind trial of propranolol with alprazolam and placebo.91 produced a less robust result in the large multicenter controlled study that followed.

is being developed for the potential treatment of several central nervous system disorders and anxiety. sertraline). the usual dietary and medication restrictions of the MAOIs are more problematic in this patient group. tricylic antidepressant. while hyperarousal. or buspirone SSRI (fluoxetine. emotional numbing. especially concerning how soon after the event treatment has to be started to offer this protection. particularly flashbacks. 278 . or agitation development of PTSD.126. Moreover. aggressivity. sertraline) or mood stabilizer (carbamazepine. and so forth.121 Posttraumatic stress disorder Benzodiazepines PTSD is a complex syndrome occurring after one or more traumatic events and involves multiple anxiety symptoms. placebo-controlled study. anxiety. O’Brien and Nutt124 hypothesized that early BZ treatment of trauma survivors may protect toward future Predominant clinical features • Intusive thoughts and flashbacks. while SSRIs and MAOIs have been tested in nonveteran samples.125 Antidepressants TCAs have been shown to be helpful in three controlled trials.123 TCAs have been tested mainly on samples of veterans with severe chronic PTSD. and avoidance behavior are scarcely affected.126 but other trials have failed to observe positive effects. including social anxiety disorder. including flashbacks. SSRI.129 but at relatively low doses compared with the two previous trials. TCA.123 but withdrawal symptoms were particularly severe. In addition.123 Early trials with combat veterans suggest that the reversible MAOI moclobemide is promising. they reported a positive effect in subjective well-being and a reduction in anxiety. or TCA (imipramine. and nightmares. irritability. irritability. paroxetine.131 First-line treatment SSRI (fluoxetine. An important finding arising from these studies is the lack of placebo response in PTSD compared with other anxiety disorders. and insomnia. assault. clonazepam.120 Pregabalin. Posttraumatic stress disorder (PTSD): therapeutic strategies. and flashbacks with no effect on numbing or avoidance in an 8-week study. and hypervigilance (Table IV). impulsivity.130 MAOIs appear to produce moderate to good clinical improvement. lithium. Imipramine (up to 300 mg/day) decreased intrusive thoughts.Pharmacological aspects High doses of gabapentin (3600 mg/day) provided encouraging preliminary results in a 14-week.127 Amitriptyline (up to 300 mg/day) has also been shown to reduce avoidance and anxiety in an 8-week trial. phobic avoidance. selective serotonin reuptake inhibitor. primarily affecting PTSD intrusive recollections.128 Desipramine failed to show any advantage over placebo in a 4-week study. The first placebo-controlled trial was conducted by Braun et al122 using alprazolam up to 6 mg/day. MAOIs have also been shown to be effective (phenelzine up to 75 mg/day) in reducing intrusive thoughts and flashbacks after 8 weeks of treatment. Although there is no established pharmacotherapy for PTSD. numbing.This disorder was first recognized after military combat. amitriptyline). or phenelzine Olanzapine Partial or no response SSRI and/or mood stabilizer (also topiramate and gabapentin) combination Add nefazodone or trazodone for concurrent sleep disorders Table IV. a follow-up compound of the GABA agonist gabapentin. especially considering the substantial comorbidity of PTSD with alcohol and drug abuse. flashbacks. insomnia • Depressive symptoms • Psychotic symptoms. there are multiple medications that seem to be effective in reducing these symptoms. BZs seem to be helpful in suppressing hyperarousal symptoms. as highlighted by Friedman. hyperarousal. nightmares. given the high incidence of substance abuse. and accidents. startle reaction. depression. valproate) Alprazolam. but the data are still controversial. but is now seen frequently after rape.Although the core symptoms of the syndrome (intrusion and avoidant/numbing symptoms) did not improve significantly compared with placebo. Open trials with alprazolam and clonazepam came to similar results. avoidance of the reminders of the event. paroxetine. impulsivity • Anxiety without severe depression. but it had no effect in the re-experiencing of intrusive thoughts and images.

and anger. 3 .123 Other drugs The anticonvulsant carbamazepine has been shown to decrease flashbacks.145-147 particularly in patients with poor impulse control. selective serotonin reuptake inhibitor.133 This has been confirmed in a placebo-controlled trial of veteran and civilian trauma victims. olanzapine) Add different typical/atypical neuroleptic (pimozide. olanzapine) Table V. including intrusive thoughts. 279 . and few data exist to date. a BZ that also affects serotonergic transmission. First-line treatment SSRI Eventually switch to a different SSRI or SRI (clomipramine or intravenous clomipramine) (Potentiation with buspirone.153 and acute.143. Buspirone (15-35 mg/day) was reported to be effective in reducing anxiety. while clonidine was largely ineffective.Cassano et al SSRIs have been observed to be helpful in open studies.139.Vol 4 .142 and there is only anecdotal evidence for improvement with trazodone.151 Some case reports with atypical neuroleptics and an open-label study with olanzapine have been positive for the treatment of the core symptoms and the psychotic symptoms that PTSD patients may exhibit. depression. haloperidol. avoidant behaviors.153 Obsessive-compulsive disorder Benzodiazepines BZs are not a first-choice treatment for OCD (Table V). nightmares.144 Lithium and valproic acid may be helpful as well.148 Open-label topiramate149 and gabapentin150 appeared effective as add-on therapy for chronic PTSD. explosiveness. with patients who failed on clomipramine showing a clinically significant response to clonazepam. 2002 Psychopharmacology of anxiety disorders . tricylic antidepressant. especially with fluoxetine up to 80 mg/day. unrelated to changes in anxiety. numbing. emotional numbing. Penava et al 135 conducted an effect-size analysis of controlled studies where fluoxetine showed the biggest effect compared with the other antidepressant and BZs studied so far.141. hyperarousal. MAOI. nightmares. haloperidol. TCA. Clonazepam. and intrusive images. psychotic symptoms Partial or no response Add mood stabilizer (lithium. sleep.154 The α1-adrenergic antagonist prazosin155 and α2-adrenergic agonists clonidine and guanfacine also provided some preliminary promising results. and impulsivity. flashbacks.152 Open-label propranolol (120-160 mg/day) improved hyperarousal. posttrauma propranolol may have a preventive effect on subsequent PTSD. benzodiazepine. clonazepam. sleep.123.140 Nefazodone (350-450 mg/day) has been shown to significantly improve most symptoms. No. doubleblind studies. and there was a significant cross-response between clomipramine and clonazepam. and depressed Predominant clinical features • Depressive symptoms. Obsessive-compulsive disorder (OCD): therapeutic strategies. gabapentin) Add BZ (clonazepam) Add MAOI or SNRI and eventually neuroleptic Add different typical/atypical neuroleptic (pimozide.Dialogues in Clinical Neuroscience . SSRI. tryptophan. Clonazepam provided an early improvement (2-3 weeks). was compared with clomipramine and clonidine in a crossover. risperidone. recurrent course with bipolar spectrum comorbidity • Highly anxious obsessional subjects • Prevalent symmetry and atypical obsession or high level of anxiety to treatment • Severe hoarding symptoms mood in three PTSD war veterans after 2 weeks of treatment.156 The first two drugs were equally effective. SNRI. risperidone. insomnia. Sertraline has also been reported effective136 in longterm treatment137. BZ. serotonin and norepinephrine reuptake inhibitor. pindolol) • Tics.138 and paroxetine (20-40 mg/day) was superior than placebo in two recent 12-week.123. double-blind study with each treatment lasting for 6 weeks.134 Approximately two thirds of patients experienced decreases in the core symptoms of PTSD including hyperarousal. monoamine oxidase inhibitor. avoidance.132. and psychosocial functioning in 11 out of 12 Vietnam veterans.

for 40 weeks. 10-year time period. nearly 40% to 60% of patients experience minimal to no improvement in symptoms with these treatments. and the selection of a drug largely depends upon personal preference. in large carefully controlled trials. Two meta-analysis suggested greater efficacy for chlorimipramine160. there has been no observed significant difference between response to higher and lower dosages for the SSRIs (eg.164 with SSRIs being better tolerated than clomipramine.168 Therefore. the degree of improvement is often incomplete. all of the SSRIs have been shown to be effective.159 Most recent controlled trials find that about 50% of patients experience a 25% to 35% drop in scale scores of OCD. This magnitude of change typically results in significant improvement in function. mistakenly thinking it was the increased dose. In fact. with few patients experiencing full symptom remission. it is difficult to choose between SSRIs.165 There was no observed difference in a trial comparing fluvoxamine. which easily can take up to a year to accomplish. A more recent meta-analysis generally failed to find any significant difference between the SRIs. without tolerance developing. during which placebo rates rose significantly. and citalopram (2060 mg/day). however. attempts to augment or improve the average response with pharmacological strategies targeting serotonergic or other neurotransmitter systems are routine. In a large extension study by Greist et al. sequential trials are frequently required. however. but despite these advances. most patients (90%) do relapse. Limited available evidence suggests that when effective pharmacotherapy is discontinued. in a double-blind way. olanzapine.162 paroxetine. principally in the patients with OCD who have comorbid tic disorders. Therapy gains with sertraline were maintained with continued medication as long as they remained on active medication.167 This clinical impression may well relate to the slow onset of effectiveness with many patients taking 10 to 12 weeks to improve (longer than 4-8 weeks for depression).Pharmacological aspects Antidepressants Pharmacological investigations have demonstrated that OCD responds selectively to drugs that act as potent inhibitors of the synaptic reuptake of serotonin. including fluvoxamine (100-300 mg/day). The 59 patients who completed this study were followed up for a second year on open-label sertraline. making any conclusion suspect. 50 and 200 mg/day sertraline). and quetiapine). these trials were performed over a 7. tryptophan.167 118 patients who had responded to 12 weeks’ treatment with either sertraline or placebo continued their treatment. although it again suggested some advantage for clomipramine. not time. The first medication demonstrated to be effective in OCD was clomipramine (150-250 mg/day) with 40% of patients (versus 4% for placebo) having a clinically significant decrease in symptoms independently of its antidepressant effect. Many patients will not respond or will partially respond to the first SSRI. it is helpful to warn patients about this from the outset. that was responsible for improvement.163 and sertraline. but will respond to another antiobsessional agent. however.157-159 Subsequently. interfering symptoms usually persist. and citalopram.171 For these reasons. in patients who do respond to SRIs.161. risperidone. Relative efficacy between the SRIs has been difficult to determine. even if the possibility of a drug interaction or the various pharmacokinetic profiles could influence the choice. clomipramine was found to have equal efficacy to fluoxetine. Therefore. Furthermore. clonidine. Dosages of these medications have often been described as being significantly higher than antidepressant dosages (eg.179 Two controlled studies were performed to test the 280 . There is no agent that is routinely effective as an augmenting agent. However. trazodone. and pindolol. paroxetine. primarily utilizing the Yale-Brown Obsessive Compulsive Scale (Y-BOCS).172 There is clear evidence of benefit for traditional neuroleptics173 and more recently the atypical neuroleptics (eg.178. and slowly titrate doses upwards to avoid side effects. sertraline (50-200 mg/day).174-177 Intravenous clomipramine has also been shown to be more effective than oral administration.170 The effectiveness of potent SRIs is now well established in the treatment of OCD. fluoxetine (20-80 mg/day).169 Another trial with paroxetine demonstrated continued efficacy for 12 months in the majority of patients. paroxetine (40-60 mg/day). 60-80 mg/day fluoxetine).166 Due to their similar effects. current practice is to continue effective pharmacotherapy for at least 1 to 2 years or indefinitely. this metaanalysis involved many of the trials mentioned above and has the same problem in interpretation. during which physicians continue to raise the patients’ doses. in several head-to-head trials. although there is some support for clonazepam. whereupon they showed additional clinical improvements. For this reason.

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